Role of TGF-beta in proliferative vitreoretinal diseases and ROCK as a therapeutic target.
Cicatricial contraction of preretinal fibrous membrane is a cause of severe vision loss in proliferative vitreoretinal diseases such as proliferative diabetic retinopathy (PDR) and proliferative vitreoretinopathy (PVR). TGF-beta is overexpressed in the vitreous of patients with proliferative vitreoretinal diseases and is also detectable in the contractile membranes. Therefore, TGF-beta is presumed to contribute to the cicatricial contraction of the membranes, however, the underlying mechanisms and TGF-beta's importance among various other factors remain to be elucidated. Vitreous samples from PDR or PVR patients caused significantly larger contraction of hyalocyte-containing collagen gels, compared with nonproliferative controls. The contractile effect was strongly correlated with the vitreal concentration of activated TGF-beta2 (r = 0.82, P < 0.0001). PDR or PVR vitreous promoted expression of alpha-smooth muscle actin (alpha-SMA) and phosphorylation of myosin light chain (MLC), a downstream mediator of Rho-kinase (ROCK), both of which were dramatically but incompletely suppressed by TGF-beta blockade. In contrast, fasudil, a potent and selective ROCK inhibitor, almost completely blocked the vitreous-induced MLC phosphorylation and collagen gel contraction. Fasudil disrupted alpha-SMA organization, but it did not affect its vitreal expression. In vivo, fasudil significantly inhibited the progression of experimental PVR in rabbit eyes without affecting the viability of retinal cells by electroretinographic and histological analyses. These results elucidate the critical role of TGF-beta in mediating cicatricial contraction in proliferative vitreoretinal diseases. ROCK, a key downstream mediator of TGF-beta and other factors might become a unique therapeutic target in the treatment of proliferative vitreoretinal diseases.
Kita
Takeshi
T
Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan.
Hata
Yasuaki
Y
Arita
Ryoichi
R
Kawahara
Shuhei
S
Miura
Muneki
M
Nakao
Shintaro
S
Mochizuki
Yasutaka
Y
Enaida
Hiroshi
H
Goto
Yoshinobu
Y
Shimokawa
Hiroaki
H
Hafezi-Moghadam
Ali
A
Ishibashi
Tatsuro
T
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000199:Actins / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D007150:Immunohistochemistry; D009130:Muscle, Smooth / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011817:Rabbits; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D018630:Vitreoretinopathy, Proliferative / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D014945:Wound Healing / Q000502:physiology; D054460:rho-Associated Kinases / Q000378:metabolism*
D000199:Actins; D047428:Protein Kinase Inhibitors; D016212:Transforming Growth Factor beta; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; C049347:fasudil